In nature, organisms of the same species usually differ from each other in some aspects, e.g., their appearance. The differences are genetically determined and are referred to as polymorphism. Genetic polymorphism is the occurrence in a population of two or more genetically determined alternative phenotypes due to different alleles. Polymorphism can be observed at the level of the whole individual (phenotype), in variant forms of proteins and blood group substances (biochemical polymorphism), morphological features of chromosomes (chromosomal polymorphism) or at the level of DNA in differences of nucleotides (DNA polymorphism).
Polymorphism also plays a role in determining differences in an individual's response to drugs. Pharmacogenetics and pharmacogenomics are multidisciplinary research efforts to study the relationship between genotype, gene expression profiles, and phenotype, as expressed in variability between individuals in response to or toxicity from drugs. Indeed, it is now known that cancer chemotherapy is limited by the predisposition of specific populations to drug toxicity or poor drug response. For a review of the use of germline polymorphisms in clinical oncology, see Lenz (2004) J. Clin. Oncol. 22(13):2519-2521; Park et al. (2006) Curr. Opin. Pharma. 6(4):337-344; Zhang et al. (2006) Pharma. and Genomics 16(7):475-483 and U.S. Patent Publ. No. 2006/0115827. For a review of the use of pharmacogenomics for the treatment of cancer, see Yan and Beckman (2005) Biotechniques 39:565-568 and Lenz (2006) Pharmacogenomics and Colorectal Cancer, Chpt. 18 in Trends in Cancer for the 21st Century, 2nd Ed., Springer.
Colorectal cancer (CRC) is the second leading lethal malignancy in the United States. In the year 2007, an estimate of 153,760 new cases will be diagnosed and 52,180 people will die from this disease (Jemal et al. (2007) CA Cancer J. Clin. 57:43-66). The current therapeutic options for patients with metastatic CRC (mCRC) are 5-fluorouracil (5-FU) based therapy regimens in combination with irinotecan (CPT-11) or oxaliplatin (de Gramont et al. (2000) J. Clin. Oncol. 18:2938-47; Douillard (2000) Lancet 355:1041-7). Despite recent advances in the chemotherapeutic treatment of mCRC, the 5-year overall survival (OS) still remains relatively poor, with a median survival of 18-21 months (Sargent et al. (2005) J. Clin. Oncol. 23:8664-70; Goldberg et al. (2006) J. Clin. Oncol. 24:4085-91). In recent years a number of new drugs and drug combinations have been evaluated for safety and efficacy in patients with metastatic CRC. Targeted agents such as Cetuximab (monoclonal antibody against the epidermal growth factor receptor) have significantly increased efficacy of chemotherapeutic regimens and have been shown to be active in several human cancers (Cunningham et al. (2004) N. Engl. J. Med. 351:337-45; Saltz et al. (2004) J. Clin. Oncol. 22:1201-8).
One of the most promising targets is the epidermal growth factor receptor (EGFR), a member of the type I receptor tyrosine kinase family. EGFR is overexpressed in a variety of malignancies, including up to 77% of CRC and is associated with tumor progression and poor prognosis (Salomon et al. (1995) Crit. Rev. Oncol. Hematol. 19:183-232; Hemming et al. (1992) J. Surg. Oncol. 51:147-52). Activation of the EGF/EGFR axis triggers multiple signaling pathways that result in endothelial cell proliferation, apoptosis, angiogenesis, and metastasis. Herbst and Shin (2002) Cancer 94:1593-611. Conversely, inhibition of the EGFR pathways with anti-EGFR monoclonal antibodies was reported to block cell cycle progression and induce apoptosis in numerous in vitro and xenograft models (Fan et al. (1993) Cancer Res. 53:4637-42; Karnes et al. (1998) Gastroenterology 114:930-9; Wu et al. (1995) J. Clin. Invest. 95:1897-905). Multiple phase II clinical trials demonstrated that Cetuximab has promising efficacy in patients with mCRC (Cunningham et al. (2004) N. Engl. J. Med. 351:337-45; Saltz et al. (2004) J. Clin. Oncol. 22:1201-8).
The Food and Drug Administration has approved the use of Cetuximab, an antibody to the epidermal growth factor receptor (EGFR), either alone or in combination with irinotecan (also known as CPT-11 or Camptosar®) to treat patients with EGFR-expressing, metastatic CRC, who are either refractory or intolerant to irinotecan-based chemotherapy. One recent study (Zhang et al. (2006) Pharmacogenetics and Genomics 16:475-483) investigated whether polymorphisms in genes of the EGFR signaling pathway are associated with clinical outcome in CRC patients treated with single-agent Cetuximab. The study reported that the cyclin D1 (CCND1) A870G and the EGF A61G polymorphisms may be useful molecular markers for predicting clinical outcome in CRC patients treated with Cetuximab.
Other polymorphisms have been reported to be associated with clinical outcome. Twenty-one (21) polymorphisms in 18 genes involved in the critical pathways of cancer progression (i.e., drug metabolism, tumor microenvironment, cell cycle regulation, and DNA repair) were investigated to determine if they will predict the risk of tumor recurrence in rectal cancer patients treated with chemoradiation (Gordon et al. (2006) Pharmacogenomics 7(1):67-88). However, to the best of Applicant's knowledge, correlation of the polymorphisms identified herein have not been correlated with clinical outcome and treatment with single agent Cetuximab or equivalent thereof.